rs104893941
Variant names:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_003900.5(SQSTM1):c.1175C>T(p.Pro392Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,614,158 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P392P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 2 hom. )
Consequence
SQSTM1
NM_003900.5 missense
NM_003900.5 missense
Scores
5
9
4
Clinical Significance
Conservation
PhyloP100: 7.87
Genes affected
SQSTM1 (HGNC:11280): (sequestosome 1) This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]
MRNIP (HGNC:30817): (MRN complex interacting protein) Enables chromatin binding activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; regulation of double-strand break repair; and response to ionizing radiation. Located in nucleoplasm. Colocalizes with Mre11 complex. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.09615874).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00133 (203/152272) while in subpopulation AMR AF= 0.0053 (81/15288). AF 95% confidence interval is 0.00437. There are 1 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 203 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SQSTM1 | NM_003900.5 | c.1175C>T | p.Pro392Leu | missense_variant | Exon 8 of 8 | ENST00000389805.9 | NP_003891.1 | |
| SQSTM1 | NM_001142298.2 | c.923C>T | p.Pro308Leu | missense_variant | Exon 9 of 9 | NP_001135770.1 | ||
| SQSTM1 | NM_001142299.2 | c.923C>T | p.Pro308Leu | missense_variant | Exon 9 of 9 | NP_001135771.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.00133 AC: 203AN: 152154Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000980 AC: 246AN: 251018Hom.: 2 AF XY: 0.000987 AC XY: 134AN XY: 135722
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GnomAD4 exome AF: 0.00143 AC: 2091AN: 1461886Hom.: 2 Cov.: 31 AF XY: 0.00139 AC XY: 1013AN XY: 727242
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GnomAD4 genome 0.00133 AC: 203AN: 152272Hom.: 1 Cov.: 33 AF XY: 0.00138 AC XY: 103AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:12Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3Uncertain:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | SQSTM1: PS3, PS4:Moderate, PM5:Supporting, PP3 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 26, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 09, 2023 | PP3, PM1 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2024 | Observed in multiple unrelated patients with Paget disease of bone (PDB), frontotemporal dementia (FTD), and/or amyotrophic lateral sclerosis (ALS) in published literature; however, variant has been observed in controls (PMID: 31475037, 26839080, 24042580, 32409511, 23417734, 35260199); Published mouse models expressing the P392L equivalent variant (P394L in the murine sqstm1 gene) developed a skeletal disorder similar to PDB; however studies using affected patient cells and a different mouse model suggest that the P392L variant may be insufficient to cause PDB on its own, and additional genetic and/or environmental factors may be required (PMID: 21515589, 18765443, 21195346, 26713335); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24899140, 15493999, 18765443, 19589897, 12857745, 26713335, 28430856, 23942205, 25241215, 33612544, 32329415, 32893041, 33325387, 34426522, 11992264, 21195346, 26839080, 24042580, 32409511, 23417734, 33015249, 30889971, 31000212, 30729484, 30671590, 30726512, 31462833, 28889094, 32978683, 29457785, 27594680, 27275741, 29948344, 29599744, 30886882, 25708934, 30594595, 15125799, 26627873, 31634910, 31616248, 32176830, 31530427, 35241069, 35260199, 21515589, 31475037, 35229101, 36327984, 35769265, 35708843, 36918542, 35355568, 36035996, 35330074, 36133075, 38493523, 37868330, 37370996, 37205240, 38123339, 36701233, 38960585, 39079071, 39122262, 38016875) - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The SQSTM1 p.P392L variant is a well-known variant and was identified in 59 of 356 proband chromosomes (frequency: 0.1657) from individuals or families with Paget’s disease of bone (PDB) and was not identified in 582 control chromosomes from healthy individuals (Laurin_2002_PMID:11992264, Hocking_2002_PMID:12374763, Seton_2016_PMID:26713335). The p.P392L variant was also identified in patients with PDB in the Dutch, Italian, French-Canadian, and Australian populations and was also shown to segregate with disease in 20 families from Quebec with PDB (Laurin_2002_PMID:11992264; Morissette_2006_PMID:17229007; Hocking_2002_PMID:12374763; Eekhoff_2004_PMID:15146436; Falchetti_2004_PMID:15125799; Good_2004_PMID:15207768). In addition to Paget’s disease of bone, the p.P392L variant has been identified in patients with Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Distal Myopathy (Fecto_2011_PMID:22084127, Teyssou_2013_PMID:23417734, Le Ber_2013_PMID:24042580, Kwok_2014_PMID:23942205, van der Zee_2014_PMID:24899140, Niu_2018_PMID:29599744). Some of these patients with ALS did not have a personal/family history of PDB or they did; one family had three affected individuals with FTD and PDB and other unaffected family members did not carry the variant (Fecto_2011_PMID:22084127, Le Ber_2013_PMID:24042580, Kwok_2014_PMID:23942205, Niu_2018_PMID:29599744). The p.P392L variant is located in the highly conserved ubiquitin-associated (UBA) domain in the p62 protein which is involved in multiubiquitin chain binding. An NMR structure of the UBA domain with the p.P392L mutant showed no effect on the interaction of the UBA domain with multiubiquitin chain binding (Ciani_2003_PMID:12857745). An in vitro assay showed the p.P392L mutation does not affect the binding properties of UBA, however it had subtle local effects on the UBA domain structure (Layfield_2004_PMID:15493999). Other in vitro functional expression studies in E. coli showed the p.P392L mutation caused loss of monoubiquitin binding and impaired K48-linked polyubiquitin binding (Cavey_2005_PMID:15765181). There are conflicting in vivo studies on mice with the p.P392L mutation and association with PDB (Hiruma_2008_PMID:18765443, Daroszewska_2011_PMID:21515589). Chamoux et al. conducted in vivo studies on mature osteoclasts from PDB patients and healthy donors that carried or do not carry the p.P392L variant. Results showed the p62 protein was significantly more expressed in PDB patient than in healthy donors, regardless of whether the p.P392L variant was present or not. However, overexpression of p.P392L mutated p62 led to the formation of more osteoclasts which contained more nuclei than non-transfected cells or cells overexpressing wild-type p62. The p62 p.P392L mutation contributed to increased activation of other proteins (Chamoux_2009_PMID:19589897). Other studies speculate environmental and genetics factors involved in the formation of disease in those with PDB and distal myopathy (Niu_2018_PMID:29599744, Kurihara_2011_PMID:21195346). The variant was identified in dbSNP (ID: rs104893941), LOVD 3.0 and ClinVar (conflicting interpretations of pathogenicity: uncertain significance by GeneDx, pathogenic by Laboratory for Molecular Medicine and Illumina, likely pathogenic by Division of Human Genetics, Children's Hospital of Philadelphia , and benign by Invitae, associated with the conditions Paget disease, Amyotrophic lateral sclerosis and/or frontotemporal dementia 1, and Frontotemporal dementia and/or amyotrophic lateral sclerosis 3). The variant was identified in control databases in 259 of 282398 chromosomes (2 homozygous) at a frequency of 0.000917 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 15 of 7228 chromosomes (freq: 0.002075), European (non-Finnish) in 173 of 128718 chromosomes (freq: 0.001344), La - |
Paget disease of bone 3 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The SQSTM1 c.1175C>T (p.Pro392Leu) missense variant is the most commonly observed SQSTM1 variant in individuals with Paget disease of bone (PDB) to date (Seton et al. 2016). Across a selection of the literature, the p.Pro392Leu variant has been identified in a homozygous state in four PDB patients and in a heterozygous state in 101 individuals with familial PDB and in 211 individuals with sporadic PDB (Laurin et al. 2002; Michou et al. 2003; Hocking et al. 2004; Lucas et al. 2005; Morissette et al. 2006; Chung et al. 2008; Rea et al. 2009; Visconti et al. 2010; Seton et al. 2016). Morissette et al. (2006) calculated the penetrance of this variant to be 50% among all age groups, and approximately 80% for individuals over the age of 60. The p.Pro392Leu variant was absent from 1186 controls but is reported at a frequency of 0.02404 in the Puerto Ricans from Puerto Rico population of the 1000 Genomes Project. This frequency is high but is consistent with the disease prevalence and reduced penetrance seen among younger individuals. Several studies identified a shared ancestral haplotype among most individuals carrying the p.Pro392Leu variant allele, indicating that the variant is likely a founder mutation in populations of Western European descent (Laurin et al. 2002; Lucas et al. 2005; Morissette et al. 2006; Chung et al. 2008; Rea et al. 2009). Functional studies demonstrated that the p.Pro392Leu variant disrupted protein interaction and reduced binding affinity for ubiquitin (Cavey et al. 2005; Rea et al. 2006; Chamoux et al. 2009; Kurihara et al. 2011; Sundaram et al. 2011). Based on the collective evidence, the p.Pro392Leu variant is classified as pathogenic for Paget disease of bone. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 29, 2019 | - - |
Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 Pathogenic:2Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 24, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Sep 20, 2021 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2014 | - - |
Amyotrophic lateral sclerosis Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Nov 10, 2022 | ACMG criteria used to clasify this variant: PS4_MOD, PM1, PP3_MOD, PM2_SUP, BS2 - |
Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2025 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 392 of the SQSTM1 protein (p.Pro392Leu). This variant is present in population databases (rs104893941, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autosomal dominant Paget disease of the bone (PMID: 11473345, 11992264, 15125799, 17229007). It has also been observed to segregate with disease in related individuals. The penetrance of this variant appears to be reduced and increases with age. In one study, the penetrance was 50% across all age groups but 17% below the age of 50 (PMID: 17229007). Of note, this variant has also been observed in individuals with frontotemporal dementia (PMID: 24899140, 24042580), amyotrophic lateral sclerosis (PMID:23417734, 23942205, 24899140, 28430856), and myopathy (PMID:29457785, 29599744), but the association with these diseases is unclear. ClinVar contains an entry for this variant (Variation ID: 8108). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SQSTM1 protein function. Experimental studies have shown that this missense change affects SQSTM1 function (PMID: 15765181, 16813535, 19589897, 21195346, 21878516). For these reasons, this variant has been classified as Pathogenic. - |
Spastic paraplegia-Paget disease of bone syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 09, 2018 | The p.Pro392Leu variant in SQSTM1 has been reported in at least 100 individuals with Paget disease of the bone (PDB) and was found to segregate with PDB in >40 individuals across 11 families (Laurin 2002, Morissette 2006, Seton 2016). In vi tro and in vivo functional studies support an impact on protein function (Layfie ld 2004, Hiruma 2008, Chamoux 2009, Kurihara 2011; Daroszewska 2018); however, s ome of these studies suggest that the variant is not sufficient to cause disease on its own, and that environmental stimuli may play a role in its phenotypic ex pression (Hiruma 2008, Kurihara 2011). This variant has also been identified in 0.14% (179/126230) of European chromosomes by gnomAD, including 2 homozygous ind ividuals (http://gnomad.broadinstitute.org). This appreciable frequency is consi stent with the reduced penetrance of PDB as well as the high prevalence of PDB i n European populations (estimates range from 0.2-10% across different patient po pulations; Morrisette 2006, Valenzuela 2017). It should be noted that this varia nt has also been reported in patients with frontotemporal dementia (FTD; van der Zee 2014, Le Ber 2013), amyotrophic lateral sclerosis (ALS; Teyssou 2013, Kwok 2014, van der Zee 2014, Morgan 2017), and myopathy (Lee 2018, Niu 2018). However , the role of the SQSTM1 gene in these disorders is not well established. In sum mary, the p.Pro392Leu variant meets criteria to be classified as pathogenic for PDB in an autosomal dominant manner with reduced penetrance. Additional data is required to determine if this variant contributes to other disorders. - |
Paget disease of bone 3;C4225326:Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jun 23, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at